Effect of continuous phase drug concentration, evaporation and partitioning on transdermal drug permeation kinetics with lipophilic vehicles

摘要

In this work the dependence of transdermal drug permeation kinetics on continuous phase drug concentration, partitioning between formulation phases, partitioning between stratum corneum and continuous oil phase and evaporation of volatile formulation components for a hydrophilic (caffeine) and a lipophilic (ibuprofen) model drug incorporated into w/o-emulsions of varying composition was investigated. The studied w/o-emulsions consisted of an oil phase into which water phase was dispersed in mass fractions of 70%, 50% and 30% (E70, E50 and E30, respectively). The oil phase consisted of a single oil component (isopropyl myristate, miglyol 812N or paraffinum liquidum) and the polymeric emulsifier Isolan PDI. Water phase contained sodium chloride and was buffered to pH 4.5 in all emulsions containing ibuprofen. Pure oil with and without emulsifier were selected as reference formulations. Transport experiments were carried out in Franz-type diffusion cells across pig ear skin at 32° under occlusive and non-occlusive C conditions with an infinite dosing of 0.3 g/cm2 and 0.7 g/cm2. Continuous phase drug concentration was determined experimentally by ultracentrifugation and theoretically by calculation taking into account drug partitioning between distinct phases. A concept for the interpretation of drug permeation was proposed that considered continuous phase drug concentration as the driving force for transdermal permeation. Drug distribution within the formulation and partitioning between stratum corneum and continuous oil phase were determined in order to gain a full understanding of the examined absorption processes. Dependence of apparent permeability coefficient Papp on fraction of drug concentration in the continuous phase was analyzed with a model taking into account the permeability coefficient of the skin Pm and the permeability coefficient of the diffusion boundary layer Pdbl. Pdbl reflects the diffusivity of the drug in the vehicle. By fitting this model to the experimental data using non-linear regression, parameter values for Pm and Pdbl were deduced. Pm values were consistent with the drug partitioning between stratum corneum and continuous oil phase. For isopropyl myristate a permeation enhancement was found in agreement with literature. Pdbl values were compared with calculated values using a literature model for diffusion in heterogeneous matrix systems. These were found in most cases to be in fairly good agreement with the Pdbl values.ududFree emulsifier present in the continuous oil phase affected neither saturation concentrationudnor continuous phase drug concentration nor transdermal absorption of the model drugs.udThickener Aerosil 200 tremendously decreased transdermal permeation of caffeine, but didudnot show any interaction with ibuprofen. A reduction of applied dose (0.3 g/cm2 instead of 0.7udg/cm2) did not significantly affect apparent permeability coefficient P-app. Evaporation patternudof all examined formulations revealed that relative water loss was independent of theuddispersed mass fractions and the employed experimental setup, but increased as the appliedudformulation dose was reduced.udFor implementing continuous phase drug concentration concept to non-occlusive conditions,uda formula was derived that considered observed water loss and permeated drug amount inudorder to calculate the resulting drug concentration in the continuous formulation phase overudtime. An increase of the drug concentration in the continuous oil phase was estimated which,udhowever, did not lead to a measurable increase of the apparent permeability coefficient.udTo conclude, the proposed concept considering continuous phase drug concentration can beudused to explain experimentally measured apparent permeability coefficient P-app for lipophilicudvehicles. Applying this concept to w/o-emulsions comprising varying mass fractions providesuda predictive tool in order to delineate the effect of physicochemical formulations parametersudand transdermal drug delivery rate, if occlusive conditions are assumed. In case of nonocclusiveudtransport conditions, however, evaporation will lead to compositional changes andudconsequently changes in continuous phase drug concentration. How these alterations willudaffect apparent permeability coefficient using a finite dose requires further investigations.